There is a growing population of IV-infected people over the age of 50 due to prolonged survival on HAART. Aging is associated with a decline in immune functions that include decreased thymic output, reduced T-cell proliferative capacity, reduced frequency of naove CD4 and CD8 T-cells, increased frequency of Tregs, constricted B- and T-cell repertoire, and increased basal levels of inflammation. The mechanisms underlying age-related decline in immune function and how these processes influence immune dysregulation in HIV-infected individuals with increasing age are unknown. microRNAs regulate diverse biological processes including cell development, differentiation, proliferation, senescence, and apoptosis, and play important roles in immunity. miRNAs are implicated in aging processes in C. elegans and mice, but their role in human aging has not been explored. Preliminary studies identified age-regulated miRNAs in human PBMC based on miRNA expression profiling of samples from middle-aged versus elderly subjects. Several of these miRNAs are important regulators of immune function, and a subset were previously shown to dysregulated in PBMC from HIV-infected individuals. This proposal will investigate the role of miRNAs in age-related immune dysfunction in HIV infection. Our working hypothesis is that changes in miRNA regulation in naove and central memory T-cell subsets contribute to age-related decline in immune system function, and are accelerated in HIV-infected individuals due to effects of HIV, immune activation, or antiviral drug toxicities. Dynamic regulation of miRNAs in the aging immune system may coordinate expression of sets of genes to protect T-cells against age-related stresses (i.e. oxidative stress, DNA damage), but this mechanism may come at the cost of impaired or dysregulated immune function. This proposal will investigate three specific aims: 1) Characterize age-regulated miRNAs in CD4 and CD8 naive and memory T cell subsets isolated from young, middle-aged, and aged individuals and determine if differences in their expression profiles in HIV- infected compared to uninfected individuals suggest accelerated aging in the immune system;2) Determine the association between age-regulated miRNAs in T-cell subsets and markers of immunological aging;3) Explore the role of miR-223 and other age-upregulated miRNAs as suppressors of CD4 T cell function that promote HIV latency in resting CD4 T cells. These studies will provide a better understanding of mechanisms that underlie the decline in immune function that occurs during aging, and how they contribute to age-related immune dysfunction in older individuals with HIV infection. PUBLIC HEALTH RELEVANCE: This proposal will investigate the role of microRNAs n age-related immune dysfunction in HIV infection. The studies will provide a better understanding of mechanisms that underlie the decline in immune function that occurs with increasing age, and how they contribute to age-related immune dysfunction in older individuals with HIV infection.